DESCRIPTION: (Applicant's Abstract) The spatial and temporal patterns of transient elevations of the intracellular concentration of free calcium ions within spines and dendrites are crucial for synapse development and maturation. Furthermore, synaptic plasticity is regulated by several neuromodulators acting on those patterns of intracellular Ca2+ concentration in both pre and postsynaptic compartments. Recent findings indicate that neurotrophins, including brain-derived neurotrophic factor (BDNF), are also necessary for synapse development, as well as for the induction and maintenance of long-term changes in synaptic strength. Although neurotrophins have been shown to induce Ca2+ elevations, the specific mechanisms involved, the source(s) of Ca2+ ions, and the consequences for synaptic development and plasticity are not known. Therefore, the delineation of the pre and postsynaptic mechanisms triggering those Ca2+ elevations is fundamental to the understanding of how neurotrophins modulate synaptic development and plasticity. The specific hypothesis to be tested is: BDNF enhances dendritic Ca2+ elevations during synaptic activity in hippocampal CA1 pyramidal neurons by the activation of the receptor tyrosine kinase (TrkB) signaling pathway. The regulation of the spatio-temporal patterns of dendritic Ca2+ elevations by BDNF is the most likely mechanism for its modulation of synaptic development and plasticity. The fundamental information gained from these experiments will integrate the role of BDNF on synaptic maturation and plasticity with the requirement of NMDA receptors and compartmentalized dendritic Ca2+ signals necessary for the induction of long-term synaptic changes in the hippocampus. The hippocampus is one of the most susceptible cortical regions to neurodegenerative diseases. Due to its role in explicit learning and memory, severe impairments in cognitive performance occur in patients suffering neurodegenerative diseases involving hippocampal areas innervated by cholinergic systems. Neurotrophins have been implicated in the maintenance of neuronal viability in adulthood, possibly underlying the reported neuroprotection and restoration of impaired brain function in neurodegenerative disorders, such as Alzheimer's disease. These neuroprotective effects have prompted significant research on their potential clinical use as therapeutic agents. Understanding the role of neurotrophins in synapse formation, maintenance and plasticity will make fundamental contributions to the development of therapeutic strategies for the improvement of cognitive functions in certain neurodegenerative diseases, such as Alzheimer's disease.